Enhancement of mitochondrial ATP production by the Escherichia coli cytotoxic necrotizing factor 1

Abstract

Mitochondria are dynamic organelles that constantly change shape and structure in response to different stimuli and metabolic demands of the cell. The Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1) has recently been reported to influence mitochondrial activity in a mouse model of Rett syndrome and to increase ATP content in the brain tissue of an Alzheimer's disease mouse model. In the present work, the ability of CNF1 to influence mitochondrial activity was investigated in IEC‐6 normal intestinal crypt cells. In these cells, the toxin was able to induce an increase in cellular ATP content, probably due to an increment of the mitochondrial electron transport chain. In addition, the CNF1‐induced Rho GTPase activity also caused changes in the mitochondrial architecture that mainly consisted in the formation of a complex network of elongated mitochondria. The involvement of the cAMP‐dependent protein kinase A signaling pathway was postulated. Our results demonstrate that CNF1 positively affects mitochondria by bursting their energetic function and modifying their morphology.

The Escherichia coli protein toxin cytotoxic necrotizing factor 1 induces epithelial mesenchymal transition

“…In conclusion, we herein corroborate the potential role of bacterial CNF1 was purified as previously described (Travaglione et al, 2014). For most experiments, cells were seeded at a density of 2 × 10 5 cells cm −2 and, 24 hr after the seeding, exposed for 4, 24, and 48 hr to 10 −10 M CNF1.…”

High yield purification and first structural characterization of the full‐length bacterial toxin CNF1

“…1,2 Conversely, the same CNF1-induced mechanisms that seem to trigger the harmful effects of these diseases (i.e., Rho GTPases activation, wide cellular actin reorganization and alteration of mitochondria homeostasis) have been exploited to relieve the symptoms of other severe neurological diseases. [14][15][16][17][18][19][20][21][22] As a result, there is a great attention for an inclusive study of this protein at the molecular level to decipher both its action as a toxin and as a potential drug. At this point, we think that the level of detail devoted to the structural characterization of the catalytic domain of the protein should be extended to the full-length CNF1.…”

“…The main effects of this process include the activation of a controlled immune response in the host and a wide reorganization of the actin cytoskeleton of the infected cell which is exploited for the bacterial uptake . CNF1 capability to directly affect Rho GTPases action and indirectly actin assembly and cellular bioenergetics has recently been exploited in the treatment of some severe neurological diseases, including Alzheimer's disease, Parkinson's disease and Rett syndrome …”

“…12,13 CNF1 capability to directly affect Rho GTPases action and indirectly actin assembly and cellular bioenergetics has recently been exploited in the treatment of some severe neurological diseases, including Alzheimer's disease, Parkinson's disease and Rett syndrome. [14][15][16][17][18][19][20][21][22] Several studies have pointed out the general structuration of CNF1 as an AB toxin, presenting two different receptorrecognition sites (an N-terminal 37LRP/67LR binding domain and a C-terminal Lu/BCAM binding domain) and a C-terminal catalytic domain catalyzing Rho deamidation. [23][24][25][26][27][28] The mechanism of internalization of this toxin is quite complex and requires its binding with both receptors, its transport via endocytosis and the release of the cleaved C-terminal domain in the cytosol after an acidic-dependent insertion of two hydrophobic regions in the endosomal membrane.…”

Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson’s disease

“…The molecule increases the ability of astrocytes to support neuronal growth and decreases their production of interleukin 1β . Moreover, CNF1 affects the activity of mitochondria, enhancing cell energy metabolism (Travaglione et al, 2014). The above-mentioned actions are relevant to the pathology of PD (Bueler, 2009;Saura et al, 2003).…”